ABSTRACT We are applying for a 1-year supplemental award in response to NIH Notice NOT-AG-20-008 ?AD/ADRD- focused supplements for NIH grants that are not focused on AD/ADRD.? The goal of the parent project of this supplement is to develop pro-resolving reparative maresin-like lipid mediators encapsulated in microparticles (MarL-Ps) to resolve chronic inflammation and impaired healing of wounds in aging. The resolution of chronic inflammation is pivotal for AD/ADRD treatment and appears to involve MarL actions. Thus, we propose in this project to reduce the MarL-P size to a nanoparticle range to create MarL encapsulated in nanoparticles (nanoMarLs) that are able to sustain MarL delivery across the blood-brain barrier (BBB) into the brain. Our immediate goal for this supplemental project is to develop our innovative nanoMarLs and to determine their ability to prevent and ameliorate AD pathogenesis. The therapeutic potential of MarLs is currently limited because MarLs are eliminated from the brain or blood in a few hours, whereas the prevention and amelioration of AD progression are long-term processes. We have recently developed a MarL carrier that uses a novel prototype of amino acid (arginine)-based poly(ester amide) protein-mimic (AA-PEA) nanoparticles that have the potential to sustain MarL delivery across the BBB. AA-PEAs are a new generation of biomaterials that are biocompatible, biodegradable, and non-toxic. Our working hypothesis is that nanoMarL treatment will resolve chronic systematic and brain-local inflammation, and may prevent or, at least, ameliorate AD pathogenesis. Our Aim is as follows. 1A) We will further optimize the nanoMarLs using preparation methods similar to those described for MarL-microparticles in the active parent award, except with a particle sizeat nano-scale for delivery across the BBB of AD-model mice. 1B) We will determine the ability of nanoMarLs modulate AD pathogenesis in AD-model mice. Overall Impact: This supplemental project will identify an innovative nanoMarL-based strategy and therapeutic that may ameliorate AD pathogenesis by studying bioactions of MarLs delivered and sustained by AA-PEA nanoparticles. The study is highly translational for the medical care of AD/ADRD. The proposed work is within the scope of the active parent award that also studies MarLs delivered and sustained by AA-PEA particles (although the parent award deals with microparticles and chronic wounds). Thus, this proposal matches the 3 criteria set out in NOT-AG-20-008 for an AD-focused supplemental grant. It only needs additional parallel studies for preparing and bio-assaying MarL encapsulated in AA-PEA nanoparticles in AD-model mice, for which we already have expertise. This supplemental award will allow us to conduct the research, publish novel results, and submit a R01 or U01 application that will further develop our nanoMarL-based modality to treat AD/ADRD. Our team has synergistic expertise in reparative pro- resolving lipid mediators, drug delivery biomaterials, and experimental studies of AD, so we are well suited to undertake this supplemental study.